Skin Health
The skin is the largest organ of the body, and, among other things, functions to protect the internal organs from external chemical, physical and pathological hazards. Normal skin is composed of an outer epidermis covering sub dermal layers, where each layer comprises different sections. The outer cornified layer of the epidermis possesses properties of strength, flexibility, high electrical impedance and dryness that retards penetration and proliferation of microorganisms. The cornified protective layer is formed by the migration of maturing keratinocytes that are formed at the junction of the dermis and epidermis.
Vitamin E (tocopherol) is an essential part of skin metabolism and is known to be important for skin health, with deficiency manifesting as a cornified, scaly delicate skin, thickened epidermis, scaling, lesions, chronic infection, inflammation and erythema. Vitamin E is the main naturally occurring lipid soluble agent protecting the skin from stress, and is the main lipid soluble agent protecting the cell membrane lipids from peroxidation.
Skin is subject to constant stress due to exposure to everyday elements—sun, wind and water. As a result, it is common for many cosmetic products such as lotions, moisturizers, shampoo and conditioners to contain vitamin E to assist in maintaining skin health. In order to assist in maintaining skin health, it is necessary for the vitamin E to reach the target area. The most direct method of achieving this targeting is to apply a topical formulation to the affected area. However, topical application of vitamin E to the skin using current formulations has variable success due to the skin's ability to erect an impenetrable barrier to many outside elements. It is important to provide for the penetration of vitamin E through the stratum corneum to the other parts of the epidermis and to the dermis.
It is believed that topical formulations using tocopherol acetate have not been able to deliver adequate tocopherol for the epidermal and dermal layers, and therefore provide little benefit. As tocopheryl acetate is a lipidic material requiring formulation with an oil in water emulsion, absorption from such a formulation is inadequate.
Skin Damage
The skin is susceptible to damage by bacteria, trauma, aging, free radicals, physical stress and chemical agents. The symptoms resulting from this damage include inflammation, erythema, swelling, photo-aging, thickening of the epidermis, acne, and wrinkling.
In response to stress, a variety of systems in the skin are believed to be activated and are also believed to regulate skin thickness. Cells in the epidermal-dermal junction maintain epidermal thickness. The nucleus of these cells controls the response to stress. When trauma occurs, oxygen permeates the epidermis and dermis and produces free radicals. It is thought that when epidermis is removed or damaged allowing increased oxygen permeation, protective mechanisms generate new epidermis. Such mechanisms are believed to involve phosphorylation of proteins generated when the oxygen concentration rises at the dermis/epidermis boundary. There is some evidence that tocopheryl phosphate is associated with proteins that are phosphorylated and become messengers that interact with the inflammatory response.
Many skin diseases involve inflammation and increased conversion of dermis to epidermis. When cells are damaged by free radicals, physical stress or chemical agents, the injury sets off a defensive inflammatory response typically characterized by four fundamental symptoms; redness, pain, heat and swelling. The inflammatory response has protective and defensive roles that serve to remove harmful microbes, toxins or foreign materials at the site of injury and restore tissue homeostasis. Within minutes of sustaining an injury there is noticeable vasodilabon with associated redness or wheal. Blood flow is improved to the damaged tissue and thereby increases available inflammatory mediators responsible for release of inflammatory immuno-modulators such as leukocytes that contribute significantly to the persistence of inflammation. During this process, the level of free radicals, pathogens and foreign bodies increases causing production of prostaglandin E2 synthesized from arachadonic acid by peroxidation. This in turn suppresses the production of interleukin 2 increasing vasodilation observed as redness or erythema.
One example of a skin condition involving epidermal thickening is scleroderma. Treatment of scleroderma primarily deals with reducing symptoms such as epidermal thickening, and involves the administration of corticosteroids, penicillamine, colchicine and various immunosuppresive drugs. Drugs used to reduce thickened epidermis associated with scleroderma often need to be used on a chronic basis and are associated with side effects. For example, colchicine is associated with gastrointestinal upset and nausea, corticosteroids is associated with fluid, electrolyte, musculoskeletal, gastrointestinal, dermatological, neurological, endocrine, ophthalmic, metabolic and psychiatric disturbances, and penicillamine is associated with renal and hepatic toxicity, hematological disturbances, gastrointestinal upset, taste changes, iron deficiency, muscular disorders, skin friability, and optical changes.
Acne
Acne vulgaris is a common inflammatory disorder of specialized follicles located exclusively on the face, chest and back, resulting in disfiguring and obstructive inflammatory lesions, scars or cysts. It is more typically known as acne and affects over 85% of adolescents and young adults. Although not clearly defined, it is basically understood that hormones, excess seburn and bacteria (Propionibacterium acnes) unite in susceptible individuals to obstruct skin follicles and lead to inflammatory processes that manifest clinically as erythematous papules, pustules or nodules. Initially, obstruction within the follicle is clinically undetectable and called microcomedones. As comedones enlarge they become clearly apparent as blackheads (open comedones) or whiteheads (closed comedones). These comedones may rupture to form erythematous papules, pustules or nodules that can develop pitted scars or mocules as the inflammation resolves.
The typical acne cycle may be described as follows: (i) increased seburn production in pilosebaceous glands; (ii) hyperkeratinization resulting in coalescence of keratinocytes in a follicle forming a plug; (iii) colonization of microorganisms produces antigens and inflammation; (iv) lipid oxidation/hydrolysis produces free radicals and increased fatty acids, which further increases inflammation due to chemo tactic responses, which promote polymorphonuclear leucocytes; (v) buildup within the follicle of keratin and seburn causes the follicle to rupture into the epidermis and dermis, as the microscopic orifice is too small for the material to discharge from the skin surface; and (vi) release of keratin and seburn into layers of the epidermis and dermis produce highly inflamed papules as described above.
Reported Developments
Compounds such as vitamins E, A, C and K, tocotrienol, and ubiquinone are reputed valuable agents as supportive therapy in managing skin conditions. It has been established that vitamin E stabilizes lysosomes, interacts with eicosanoids to reduce prostaglandin E2 synthesis and increases interleukin 2 production resulting in anti-inflammatory and immunostmulating effects. Interleukin 2 (IL-2) production is known to increase mitosis and cytokines including activated T cells, thereby augmenting a rapid immune response to a particular antigen. This phenomenon is measurable within 48 to 72 hours after initiation and the likely source of the clinical benefits noted for vitamin E. These effects require adequate levels of vitamin E in an appropriate form, to be delivered to dermal layers to produce the required benefit.
For many dermatological conditions, Vitamin E therapy has however not been substantiated by human studies. Effective delivery of tocopherol and other poorly absorbed or soluble compounds required to initiate a beneficial effect can be difficult to achieve and delivery of any reproducible benefit requires accumulation of an effective concentration of the compound. Further, vitamin E has even been associated with local adverse reactions including papular and follicular dermatitis. Topical and oral application of the Vitamin E acetate derivative, tocopheryl acetate, has provided inconsistent results for the treatment and/or prevention of UV damage, skin cancer formation, immunosuppression in animals, the associated erythema, edema and skin sensitivity of sunburn, skin roughness, length of facial lines, wrinkle depth and wound healing.
Acne treatments presently available for use are designed to inhibit one or more of the following factors, namely, (i) increased seburn, (ii) hyperkeratinization, and (iii) inflammation and inhibition of microorganisms. Examples of current active ingredients are the oxidant, benzoyl peroxide (antimicrobial), retinoids (reduction in keratinization by promoting cell turnover, normalizing keratinization of the pilosebaceous follicle, preventing obstruction, indirectly reducing inflammatory lesions and comedogenesis.), azelaic acid (inhibits keratinization, promotes cell turn-over and is mildly effective against microorganisms), salicylic acid (antimicrobial, seburn reducer and anti keratolytic) and sulfur. Current acne treatments commonly involve use of topical preparations of these agents as well as systemic antibiotics. These preparations have an antibacterial effect and reduce inflammation.
Exemplary antibiotics incorporated in compositions includes the lincomycin family, erythromycin and tetracycline. Acne treatment compositions containing benzoyl peroxide are also known. Antibiotic-containing compositions are known which also include anti-inflammatory steroids. Attempts to improve the effectiveness of topical antibiotic compositions for use in the treatment of acne have taken a number of approaches. One approach is the use of skin-penetrating vehicle compositions that reportedly increase the skin's absorption of a physiologically active substance, including antibiotics. However, not all penetrating agents in combination with antibiotics are effective for the treatment of acne. For example, the use of a skin-penetrating vehicle results in an effective anti-acne composition with erythromycin but not with tetracycline. A further approach relates to the use of a composition containing two different active agents, such as erythromycin and Vitamin A acid or benzoyl peroxide.
The reported topical anti-acne methods and compositions exhibit the disadvantages of limited effectiveness and frequent excessive adverse skin reactions. These treatments all have their drawbacks. For example, when benzoyl peroxide (a source of free radicals) is applied in acne treatment, scaliness results, indicating that free radicals may cause additional epidermal stress.
Sun Damage
Exposure to ultraviolet light and environmental stress and their combined detrimental effects of skin and even hair have been known for some time. Environmental stress in combination with UV light produces free radicals which are potent highly reactive peroxidase toxins which damage tissue cells leading to considerable skin conditions such as carcinogenesis and photoaging. Current knowledge in the areas of photobiology and photodermatology show that protection against the effects of UV light (in the range of 290-400 nm) is crucial to avoid the effects of sunburn, pigmentation, photoaging (solar elastosis), solar keratosis, skin cancers (melanoma and carcinoma) as well as immuno-suppression.
The common use of broad-spectrum sunscreens which absorb UV light in the range of 290-400 nm is reflected in the myriad of products available in the marketplace. Although many formulators have included tocopherol as the acetate ester, it is not known how the acetate group is removed to allow the free tocopherol to become involved in skin metabolism. It is known that free tocopherol may be inflammatory and it has been found that poor dietary intake of tocopherol leads to sun-sensitive skin.
New Products
In our co-pending international patent application no PCT/AU01/01476 we disclose a composition comprising the reaction product of:                (a) one or more phosphate derivatives of one or more hydroxylated actives; and        (b) one or more complexing agents selected from the group consisting of amphoteric surfactants, cationic surfactants, amino acids having nitrogen functional groups and proteins rich in these amino acids.        
The hydroxylated actives include the sub-group of electron transfer agents. The content of PCT/AU01/01476 is referred to and incorporated herein.